Several monoclonal antibodies with phosophocholine (PC) specificity confer species-specific protection against virulent encapsulated pneumococci of several types. The cell-wall polysaccharide (C-Ps) is most likely to be the pneumococcal structure reacting with these PC antibodies. The C-Ps is of low molecular weight (c.a. 10,000) composed of a hexasaccharide repeating unit containing a ribitol phosphate ester at its reducing end and is non-immunogenic. The Vi capsular polysaccharide (Vi-P) is a potential protective antigen of Salmonella typhi, the causative agent of typhoid fever. The Vi alone, despite its unusually high molecular weight, is a poor immunogen in adult volunteers. Heterofunctional reagents, N-succinimidyl 3-(2-pyridilthio)-propionate (SPDP) and succinimidyl 3-(2-iodoacetamide) (SIP) have been studied to devise methods for synthesis of polysaccharide-protein conjugates that could be considered for human use. The N-hydroxysuccinimide ester is the more reactive of the two functional groups of SPDP; accordingly, carrier proteins were derivated to about 6 moles SPDP/mole protein. No conformational change in the derivatized protein could be detected by circular dichroism measurement. The C-Ps was derivatized via its amino group with SPDP also. The Vi poly was then reacted with cystamine in the presence of a water-soluble carbodiimide to create a disulphide bridge. The disulfide derivatives of both C-Ps and Vi-Ps were reduced and the newly formed alipathic thiol groups were then allowed to react with the protein-SPDP derivative under thiol-disulfide exchange to form the disulfide linked Ps-protein conjugate. The resultant C-Ps and Vi-Ps-protein conjugates were considerably more immunogenic than the polysaccharides alone and are under study for their protective activites and as candidates for clinical studies.